Chimeric cytokine receptors and encoding nucleic acids

1. A chimeric cytokine receptor (CCR) comprising a first and a second chimeric transmembrane polypeptides, wherein:

(i) the first chimeric transmembrane polypeptide comprises:

(a) a first exodomain which comprises an antigen-binding domain of an antibody which binds a first epitope of a ligand;

(b) a first transmembrane domain; and

(c) a first cytokine receptor endodomain; and

(ii) the second chimeric transmembrane polypeptide comprises:

(a) a second exodomain which comprises an antigen-binding domain of an antibody which binds a second epitope of the ligand;

(b) a second transmembrane domain; and

(c) a second cytokine receptor endodomain;

wherein the ligand is a tumour secreted factor; and

wherein the first cytokine receptor endodomain or the second cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain; and wherein the other cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor.

2. A chimeric cytokine receptor (CCR) comprising a first and a second chimeric transmembrane polypeptides, wherein:

(i) the first chimeric transmembrane polypeptide comprises:

(a) a first exodomain which comprises a heavy chain variable domain (V H ) of an antibody that binds to the ligand;

(b) a first transmembrane domain; and

(c) a first cytokine receptor endodomain; and

(ii) the second chimeric transmembrane polypeptide comprises:

(a) a second exodomain which comprises a light chain variable domain (V L ) of the antibody that binds to the ligand;

(b) a second transmembrane domain; and

(c) a second cytokine-receptor endodomain;

wherein the ligand is a tumour secreted factor; and

wherein the first cytokine receptor endodomain or the second cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain; and wherein the other cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor.

3. A chimeric cytokine receptor according to claim 1 , wherein the ligand is a tumour secreted factor selected from: prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), vascular endothelial growth factor (VEGF), and CA125.

4. The CCR according to claim 1 , wherein the antigen-binding domains of the first exodomain and the second exodomain each comprises a single-chain variable fragment (scFv) that binds to the ligand.

5. The CCR according to claim 1 , wherein the antigen-binding domains of the first exodomain and the second exodomain each comprise a single-chain variable fragment (scFv) which bind to different prostate-specific antigen (PSA) epitopes.

6. The CCR according to claim 2 , wherein the first exodomain comprises a VH of an antibody that binds to PSA; and wherein the second exodomain which comprises a VL of the antibody that binds to PSA.

7. The CCR according to claim 1 ,

wherein the first chimeric transmembrane polypeptide further comprises a first spacer connecting the first exodomain and the first transmembrane domain; and

wherein the second chimeric transmembrane polypeptide further comprises a second spacer connecting the second exodomain and the second transmembrane domain.

8. The CCR according to claim 7 , wherein the first spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk; and wherein the second spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk.

9. The CCR according to claim 2 ,

wherein the first chimeric transmembrane polypeptide further comprises a first spacer connecting the first exodomain and the first transmembrane domain; and

wherein the second chimeric transmembrane polypeptide further comprises a second spacer connecting the second exodomain and the second transmembrane domain.

10. The CCR according to claim 9 , wherein the first spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk; and wherein the second spacer comprises an IgG1 Fc region, an IgG1 hinge, or a CD8 stalk.

11. A chimeric cytokine receptor according to claim 2 , wherein the ligand is a tumour secreted factor selected from: prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), vascular endothelial growth factor (VEGF), and CA125.

12. A nucleic acid construct which encodes a CCR according to claim 1 , the nucleic acid construct comprising a first nucleic acid sequence encoding the first chimeric transmembrane polypeptide and a second nucleic acid sequence encoding the second chimeric transmembrane polypeptide, the nucleic acid construct having the structure:

AgB1-spacer1-TM1-endo1-coexpr-AbB2-spacer2-TM2-endo2

in which

AgB1 is a nucleic acid sequence encoding the first exodomain which comprises the first antigen-binding domain;

spacer1 is a nucleic acid sequence encoding a spacer between the first exodomain and the first transmembrane domain;

TM1 is a nucleic acid sequence encoding the first transmembrane domain;

endo1 is a nucleic acid sequence encoding the first cytokine receptor endodomain;

coexpr is a nucleic acid sequence enabling co-expression of the first chimeric transmembrane polypeptide and the second chimeric transmembrane polypeptide;

AgB2 is a nucleic acid sequence encoding the second exodomain which comprises the second antigen-binding domain;

spacer2 is a nucleic acid sequence encoding a spacer between the second exodomain and the second transmembrane domain;

TM2 is a nucleic acid sequence encoding the second transmembrane domain;

endo2 is a nucleic acid sequence encoding the second cytokine receptor endodomain.

13. A vector comprising a nucleic acid construct according to claim 12 .

14. A method for making a cell which comprises a chimeric cytokine receptor, the method comprising introducing into an isolated cell: the nucleic acid construct of claim 12 or a vector comprising said nucleic acid construct.

15. An isolated cell which comprises a chimeric cytokine receptor according to claim 1 .

16. An isolated cell which comprises a chimeric cytokine receptor according to claim 2 .

17. An isolated cell according to claim 15 , which also comprises a chimeric antigen receptor.

18. A pharmaceutical composition comprising a plurality of cells according to claim 15 .

19. A pharmaceutical composition comprising a plurality of cells according to claim 16 .

20. A kit which comprises:

i) a vector comprising a nucleic acid sequence encoding the first chimeric transmembrane polypeptide of claim 1 ; and

ii) a vector comprising a nucleic acid sequence encoding the second chimeric transmembrane polypeptide according to claim 1 .

21. A kit according to claim 20 which also comprises a vector comprising a nucleic acid sequence encoding a chimeric antigen receptor.

22. A kit comprising the vector according to claim 13 and a vector comprising a nucleic acid sequence encoding a chimeric antigen receptor.